Biological and clinical aspects of plasminogen activator inhibitor type 2

Kruithof, EK; Baker,; Bunn, C. L.

doi:10.1182/blood.v86.11.4007.bloodjournal86114007

Cited by 277 publications

(200 citation statements)

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“…The leucocytes probably contribute only marginally to the changes in plasma levels of these two agents in septic shock. In contrast, normal plasma rarely shows u-PA activity and does not contain detectable amounts of PAI-2, though it is present in plasma in normal pregnancy and in some neoplastic or other states (Kruithof et al, 1995). In this study of severe sepsis patients, u-PA antigen levels rose and PAI-2 appeared in the plasma while levels of these agents in mononuclear cell fractions fell; indeed, u-PA and PAI-2 were sometimes no longer detectable in the mononuclear fraction in the sepsis patients.…”

Section: Discussionmentioning

confidence: 93%

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Robbie

Dummer²,

Booth

et al. 2000

Br J Haematol

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Summary. Proteins influencing plasminogen activation to plasmin, namely plasminogen activators tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their principal inhibitors, plasminogen activator inhibitor 1 (PAI-1) and PAI-2, were measured in the plasma, the polymorph and mononuclear cell fractions taken from patients with major sepsis who were entering a general intensive care unit. The purpose of this study was to elucidate the factors favouring the persistence of fibrin in the microvasculature and thus contributing to multiple organ failure. Levels of u-PA antigen in plasma rose in sepsis and u-PA activity, not detectable in normal plasma, appeared. Levels of u-PA antigen in the cell fractions fell concomitantly. t-PA antigen in plasma and in the mononuclear cell fraction rose in sepsis, but t-PA activity was not detectable. Plasma PAI-1 antigen levels were strikingly raised in sepsis, presumably accounting for the complete neutralization of t-PA activity. PAI-2 antigen, not normally detected in plasma, appeared in the plasma of some patients, whereas it disappeared from the cellular fractions. Appearance of PAI-2 in plasma was associated with non-survival of the patient. The observations indicate that all the agents involved in plasminogen activation are released into the plasma in major sepsis. The levels of PAI-1 reached were quantitatively sufficient to suppress all activity of the released t-PA, but the inhibitors did not prevent expression of u-PA activity in the circulation. Circulating active u-PA and PAI-2 in the plasma of patients with severe sepsis may represent material originating from leucocytes. Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure.

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Section: Discussionmentioning

confidence: 93%

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Robbie

Dummer²,

Booth

et al. 2000

Br J Haematol

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“…This observation is currently being followed up by further investigation. As a member of the serpin supergene family, PAI-2 is presumed to function as a regulator of plasminogen activation, although its exact biological function is unclear (17,18). Interestingly, protease nexin-1 was recently identified as upregulated in scleroderma (11) PN-1 also inhibits plasmin and the plasminogen activator urokinase (12).…”

Section: Discussionmentioning

confidence: 99%

High plasminogen activator inhibitor type 2 expression is a hallmark of scleroderma fibroblasts in vitro

Kessler-Becker

Smola

Krieg

et al. 2004

Experimental Dermatology

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Systemic scleroderma is a chronic disease, which leads to fibrosis of the skin and internal organs. Fibroblasts obtained from patients with this disease demonstrate an activated state in culture. We, in this study, report strong, constitutive overexpression of plasminogen activator inhibitor type-2 (PAI-2) in scleroderma fibroblasts and demonstrate that this induction observed at the mRNA and protein level is dependent on serum addition. Induced PAI-2 protein levels were restricted to the non-glycosylated 47-kDa form, which is located intracellularly. Induction was stable for at least 12 passages. No modulation by fibrogenic cytokines--for example, transforming growth factor-beta1 or connective tissue growth factor--or by antagonizing IL-1 receptors was observed. The data indicate that scleroderma fibroblasts are more sensitive to the induction of PAI-2 expression than control fibroblasts by a presently unknown factor in serum.

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“…Hence, post-transcriptional regulation of the PAI-2 mRNA transcript involves an interaction between closely spaced adenylate-uridylate elements in a manner analogous to the post-transcriptional regulation of oncogenes and cytokines. activator [5,6], it exists primarily as a nonglycosylated intracellular protein. Over the past decade, evidence has accumulated to suggest a role for PAI-2 in intracellular events associated with apoptosis [7][8][9][10][11], proliferation and differentiation [4,12], and the innate immune response [7,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The plasminogen activator inhibitor 2 transcript is destabilized via a multi‐component 3′ UTR localized adenylate and uridylate‐rich instability element in an analogous manner to cytokines and oncogenes

et al. 2010

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Plasminogen activator inhibitor type 2 (PAI‐2; SERPINB2) is a highly‐regulated gene that is subject to both transcriptional and post‐transcriptional control. For the latter case, inherent PAI‐2 mRNA instability was previously shown to require a nonameric adenylate‐uridylate element in the 3′ UTR. However, mutation of this site was only partially effective at restoring complete mRNA stabilization. In the present study, we have identified additional regulatory motifs within the 3′ UTR that cooperate with the nonameric adenylate‐uridylate element to promote mRNA destabilization. These elements are located within a 74 nucleotide U‐rich stretch (58%) of the 3′ UTR that flanks the nonameric motif; deletion or substitution of this entire region results in complete mRNA stabilization. These new elements are conserved between species and optimize the destabilizing capacity with the nonameric element to ensure complete mRNA instability in a manner analogous to some class I and II adenylate‐uridylate elements present in transcripts encoding oncogenes and cytokines. Hence, post‐transcriptional regulation of the PAI‐2 mRNA transcript involves an interaction between closely spaced adenylate‐uridylate elements in a manner analogous to the post‐transcriptional regulation of oncogenes and cytokines.

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Biological and clinical aspects of plasminogen activator inhibitor type 2

Cited by 277 publications

References 0 publications

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

Plasminogen activator inhibitor 2 and urokinase‐type plasminogen activator in plasma and leucocytes in patients with severe sepsis

High plasminogen activator inhibitor type 2 expression is a hallmark of scleroderma fibroblasts in vitro

The plasminogen activator inhibitor 2 transcript is destabilized via a multi‐component 3′ UTR localized adenylate and uridylate‐rich instability element in an analogous manner to cytokines and oncogenes

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